Optical Method And Device For Modulation Of Biochemical Processes In Adipose Tissue

ABSTRACT

Optical methods and devices are provided for the reduction of the lipid content of adipocytes without significant heat or intolerable adverse effect on the cells and their surrounding tissues. The optical method and device can be used to irradiate adipose tissue through the skin with non-thermal and non-destructive effects by application of near infrared (NIR) irradiation at selected wave bands in selected ranges to affect modulation of innate enzymatic processes involved in lipolysis, lipogenesis, leptin secretion, adiponectin secretion, and/or glucose absorption.

RELATED APPLICATIONS

This patent application claims priority to U.S. provisional applicationSer. No. 60/761,717, filed on Jan. 24, 2006, and U.S. provisionalapplication Ser. No. 60/781,260, filed on Mar. 9, 2006, the contents ofboth of which are expressly incorporated herein by reference.

FIELD OF THE DISCLOSURE

This disclosure relates to an optical method and device for generatinginfrared optical radiation in selected wavebands over large skin areas,to modulate adipocyte's lipolytic and lipogenic energy metabolism insubcutaneous tissues. The method and device of the disclosure can beused (alone) during exercise, or in combination with pharmacologicalmeans to biochemically alter triglyceride levels in adipocytes.

BACKGROUND

Obesity is a disorder of multiple etiologies, with an onset anddevelopment in human beings that has been recognized as having genetic,environmental, and behavioral factors. Obesity is a significant healthproblem in the developed world and is becoming an increasingly largerproblem in the developing world. For example, in the American adultpopulation, one out of three people is considered obese. Obesity isdefined by the United States Centers for Disease Control and Prevention(CDC) as an excessively high amount of body fat or adipose tissue inrelation to lean body mass and overweight as an increased body weight inrelation to height, when compared to some standard of acceptable ordesirable weight. The CDC alternatively defines overweight as a personwith a body mass index (BMI) between 25.0 and 29.9 and obesity isdefined as a BMI greater than or equal to 30.0. Obese and overweightmammals suffer from increased joint problems, increased rates of highblood pressure, and high cholesterol. Increased weight is alsoassociated with heart disease, stroke and diabetes. In 1998, forexample, consumers spent $33 billion in the United States forweight-loss products and services with very little success (Serdula, etal., Prevalence of Attempting Weight Loss and Strategies for ControllingWeight, JAMA 282:1353 1358, 1999). Thus, obesity and its associatedcomplications continue to be a major problem throughout the worldwidehealth care system.

Excessive adipose tissue in the human body, resulting from eithergenetic or environmental factors, will cause a variety of additionalsymptoms associated with chronic disease states. These disease statesinclude, but are not limited to, hyperlipidaemia, coronaryatherosclerosis, severe carbohydrate intolerance, gout, gall bladderdisease, degenerative arthritis, cancer, and infertility.

Currently there are no real cures or non-invasive treatments forobesity. Of the currently known techniques for treating obesity, themost prevalent are pharmacological attempts to suppress appetite or toinhibit intestinal absorption of nutrients. Pharmacological solutions tothe problem of obesity generally take one of three different approaches:

1) Pharmacological approach to affect the brain;

2) Pharmacological approach to affect lipid absorption during meals; and

3) Pharmacological approach to affect fat cells per se.

A significant drawback to these approaches is that with the use of anydrug to affect these mechanisms, there are a myriad of potential sideeffects, such as potential central nerves system (CNS) problems andproblems with absorption of critical fat and fat-soluble solublenutrients, that contribute to the early termination of such therapies.Available pharmacotherapies have included Sibutramine, Orlistat™,fenfluramine and dexfenfluramine. Fenfluramine and dexfenfluramine werewithdrawn from the market in 1997 because of associated cardiacvalvulopathy (Connolly, et al., Valvular Heart Disease Associated WithFenfluramine-Phentermine, New Engl J Med 337 581588, 1997).Consequently, many health care professionals are reluctant to usepharmacotherapy in the management of obesity. Complimentary approachesto pharmacotherapy may therefore be of great interest to the public.

There are other moderately effective approaches for weight loss ortreating obesity, such as behavioral modification, diets, and surgery.To date, the results of all of these approaches have beenunsatisfactory, and usually only a moderate proportion of adiposereduction is achieved, but rarely maintained. Although behavioralmodification and dietary restriction might be the most desirable methodsfor weight loss, long-term success of dietary regulation is low becauseof noncompliance. The loss of motivation to change behavioral anddietary habits necessary to consume less fat and fewer calories resultsin regaining weight.

Of surgical methods available, suction lipectomy, commonly known asliposuction, is the most common procedure for removing subcutaneous fatin the body. In general, the procedure involves the use of a specialtype of curette or cannula which is coupled to an external source ofsuction. An incision is made in the target area and the fatty tissue isessentially vacuumed from the patient's body. This procedure has itsdisadvantages, however, because the fat is relatively difficult toseparate from the surrounding tissue. Such separation often causesexcessive bleeding and damage to adjacent tissue or muscles. Other thancausing collateral damage to surrounding muscle, blood vessels, skin,nerve, and subcutaneous tissues, liposuction can result in unattractiveloose skin, postoperative hemorrhagic complications, pain, trauma,infection, and even death.

In addition to physical injuries associated with liposucion, it has beenexperimentally and clinically shown that the removal of large amounts ofabdominal subcutaneous fat via liposuction does not appreciably alterthe levels of circulating mediators of inflammation, that are almostcertainly involved in the development of insulin resistance, Diabetesand coronary heart disease.

Adipose tissue is now documented as a significant endocrine organ thatproduces numerous bioactive proteins, including interleukin-6, tumornecrosis factor (alpha), and adiponectin. The production of adiponectinby adipose tissue can improve insulin sensitivity and inhibit vascularinflammation, while interleukin-6 and tumor necrosis factor (alpha) areknown to cause insulin resistance, diabetes, atherosclerosis by damaginginsulin signaling, increasing hepatic synthesis of C-reactive protein,and increasing systemic inflammation. As stated above, since it has beenexperimentally and clinically shown that the removal of large amounts ofabdominal subcutaneous fat via liposuction does not appreciably alterthe levels of circulating mediators of inflammation (markers of insulinresistance, diabetes and coronary heart diseas) there is a need inmedical therapy to achieve a device and therapy that can augmentnaturally occurring lipolytic activity.

Weight-loss that is achieved by conventional obesity treatments (dietand exercise) decreases plasma concentrations of C-reactive protein,interleukin-6, and tumor necrosis factor-alpha and increases theconcentration of adiponectin. In stark contrast, liposuction does notsignificantly change the plasma concentrations of any of these markers.Additionally, fat removal by liposuction has been shown to decreaseplasma leptin concentration, which is a marker of adipose-tissue mass,which is not desirable as it has been implicated as a potent appetitesuppressant.

Despite its undesirable side-effects, liposuction is still being usedextensively. Various new methods have been devised to augment theprocedure by taking advantage of the ultrasonic vibrations or laserenergy to physically melt the fatty tissue so that it can be emulsifiedand aspirated through the liposuction probe. These ultrasonic probeshave reduced the physical exertion required by the surgeon to removefatty tissue, increased the speed of the operation and reducedcollateral damage created at the incision point. One problem with theseprobes, however, is excess heat generation at the distal tip of theprobe, which can readily be in excess of the temperature required formelting the fatty tissue. This excess heat often results in burning oftissue, damaging muscles or blood vessels, and even penetratingmembranes such as the skin or the peritoneum that covers most of theintra-abdominal organs.

Among the methods that exploit laser energy to remove unwanted fat, U.S.Pat. Nos. 6,605,080 and 7,060,061 issued to Altshuler, et al. representan alternative approach in which laser energy is externally applied tothe skin to heat and melt fat tissues in epidermis and subcutaneouslayers below. These patents disclose the use of near infrared radiationto heat-liquefy fat cells, after which the lipid pool is removed fromthe subcutaneous area by aspiration. Because of the considerable heatgeneration that results from the techniques, e.g., up to 70° C., at orin the fat tissue, a special cooling mechanism must be in place toprevent potential temporary skin damage or permanent scarring, withpermanent scarring occurring primarily in the dermis. These methodspresent other limitations and potential adverse thermal effects ontissue above the lipid-rich tissue under treatment, includingblistering, peeling, and depigmentation.

Therefore, there remains a need for an improved non-invasive method anddevice for reducing fat and alleviating obesity without excessive heatdeposition at the site of treatment; a technique which does not sufferfrom the noted limitations of the background art; and a method anddevice that can be utilized by the general public with convenience andease.

SUMMARY

The present disclosure addresses the limitations noted for thebackground art and provides a method and device for reducing the levelof fat or lipid in adipocytes without significant generation of heat oran intolerable adverse effect to the skin or surrounding tissue. Ingeneral, a target site on an individual is irradiated with a nearinfrared radiation in a first wavelength band or range from about 905 nmto about 945 nm and/or a second wavelength band or range from about 850nm to about 879 nm at a suitable power dosimetry, e.g., from about 0.015W/cm² to 1 W/cm², to modulate (e.g., potentiate or increase) innate, andalready occurring, biochemical processes of adipocytes in the targetsite. Preferably, the wavelength band of the optical radiation rangesfrom about 925 nm to about 935 nm. Each of the wavelength bands may beused to irradiate the target site alone or in combination with the otherband, sequentially or simultaneously in tandem. The optical radiationcan be collimated, for example in applications where an incoherent lightsource is used to generate the desired wavelengths bands.

In exemplary embodiments, the optical radiation can be provided to thetarget site for a time period of about 10 to about 120 minutes;preferably, for a period of about 15 to about 100 minutes; or morepreferably, for a period of about 20 to 80 minutes. Other applicationstimes may also be used.

As described herein, the techniques, methods, devices, and systems ofthe present disclosure, may be referred to as Low Dosimetry OpticalAdipocte Modulation (LDOAM); certain features of the embodiments mayalso be referred to as Near Infrared Microbial Elimination Laser Systems(NIMELS). In accordance with exemplary embodiments of the disclosure,the LDOAM dosimetry can provide an energy density from about 10 J/cm² toabout 10,000 J/cm² at the skin surface above the adipose tissue;alternatively, the provided energy density is from about 50 J/m² toabout 8,000 J/cm² at the skin surface above the adipose tissue; oralternatively, the energy density is from about 100 J/cm² to about 5,000J/cm² at the skin surface above the adipose tissue.

According to aspects of the disclosure, the biochemical processesmodulated by the LDOAM optical dosimetry can include, but are notlimited to, lipolysis and lipogenesis. Preferably, these processesalready are in progress when LDOAM is used, e.g., as would be the casewhen a person is participating in sport and exercise activities or whensuch processes are initiated or facilitated by pharmacological means,with or without exercise.

In exemplary embodiments of the disclosure, LDOAM radiation is generatedby Light Emitting Diode (LED) arrays or by arrays of super-luminousLEDs. Preferably, LEDs are arrayed with aspheric collimating lenseswithin a body wrap. Alternatively, or in addition, suitable laser diodesmay be used.

Other aspects of the present disclosure provide a device including oneor more suitable optical light sources, such as LED arrays, forgenerating LDOAM radiation. In exemplary embodiments of this aspect ofthe invention, LED arrays with one or more aspheric collimating lensesare configured and arranged within an article of clothing. Such articleof clothing can include means for attaching to a power source (e.g., asuitable power connection) and can be worn by a person while usingsports or exercise equipment (i.e., treadmill, bike, or weights) tofacilitate fat reduction. The power source can operate by battery orelectricity.

Additional functionality, advantages, and embodiments of the disclosureare described in the following description and included drawings.

It is to be understood that both the foregoing general description andthe following detailed description are exemplary and explanatory onlyand are not restrictive of the disclosure, as claimed.

BRIEF DESCRIPTION OF THE DRAWINGS

Aspects of the disclosure may be more fully understood from thefollowing description when read together with the accompanying drawings,which are to be regarded as illustrative in nature, and not as limiting.The drawings are not necessarily to scale, emphasis instead being placedon the principles of the disclosure. Where applicable, the samereference numbers are used throughout the drawings to refer to the sameor like parts or features. In the drawings:

FIG. 1 is a flow chart diagram depicting enzymatic steps involved in thebiochemical process of lipolysis in a human adipocyte.

FIG. 2 is a flow chart diagram illustrating enzymatic steps of thebiochemical processes of lipogenesis and lipolysis occurring in humanadipocytes.

FIG. 3 is a diagram showing the optical absorption properties of theskin dominated by the absorption for protein (collagen), melanin,hemoglobin, and water.

FIG. 4 is a diagram presenting the ratio of the scattering coefficient(μs) over the absorption coefficient (μa) in human skin of opticalradiation from about 400 nm to about 1800 nm; optical radiation at thethree near infrared wavelengths that have the highest absorption inadipose tissue or fat are emphasized.

FIG. 5 is a perspective view of an LED array above a collimating lens,in accordance with the disclosure.

FIG. 6 is a perspective view of optical energy being collimated with acollimating lens having a short focal length.

FIG. 7 is a graph presenting the effect of spot size (beam diameter) onillumination zone fluence and skin penetration.

FIG. 8 is a diagram depicting various biochemical pathways and factorsinvolved in the control of adipose tissue lipolysis.

FIG. 9 is a view of multiple LED arrays wherein each LED has a separateaspheric collimating lens on a dispersion belt, according to thedisclosure.

FIGS. 10A and B show an optical energy dispersion belt or bandage foruse as a treatment to enhance the efficiency of fat metabolism duringaerobic exercise or digestion. In 10B the LDOAM device is connected to apower supply, in accordance with the current disclosure.

FIGS. 10C through E, each show an optical energy dispersion belt orbandage connected to a power supply during aerobic exercise, inaccordance with the current disclosure.

FIG. 11 is an exemplary diagram showing that the activation barrier to abiochemical reaction (such as lipolysis) can be lowered by using aradiation with the wavelength of about 870 and/or about 930 nm at thedefined dosimetry.

FIG. 12 is the absorption spectrum of water with maximum absorptionbeing at about 950 nm.

DETAILED DESCRIPTION

Reference will now be made in detail to exemplary embodiments of thepresent disclosure, an example(s) of which is (are) illustrated in theaccompanying drawings. As noted previously, the same reference numbersare used throughout the drawings, where applicable, to refer to the sameor like parts or features.

The present disclosure relates generally to a method and device forirradiating adipose tissue that is already undergoing biochemicallipolysis, and more specifically adipocyte cell membranes, withnon-thermal and non-destructive effects by application of near infrared(NIR) radiation at desired wavelengths to effect modulation of alreadyoccurring enzymatic processes within the adipocyte, e.g., duringexercise or digestion. According to certain embodiments of thedisclosure, these processes may already be in progress, e.g., by sportand exercise activities, digestion, or by pharmacological means, whenoptical radiation is applied. Certain aspects of the disclosure providea method and/or device for the selective modulation of adipocytemetabolism in subcutaneous fat by using light in specific NIR bands orspectral ranges to effect biochemical modulation of adipocytes overlarge cutaneous area during exercise or digestion without detrimentalphotothermal effects, photothermal alteration and/or photothermaldestruction of any part of the adipocyte, adipocyte cell membrane oradipose tissues. As described in further detail herein, suitable lightsources can include, for example, light emitting diodes (LEDs) orsuper-luminous light emitting diodes (LEDs), or other suitable lightsources generating radiation in selected wavelength bands. As describedherein, such techniques, methods, and systems, may be referred to as LowDosimetry Optical Adipocte Modulation (LDOAM); certain features of theembodiments may also be referred to as Near Infrared MicrobialElimination Laser Systems (NIMELS).

Generally stated, aspects of the present disclosure can provide a methodand system useful for irradiating adipose tissue to effect modulation ofalready occurring biochemical processes within the adipocyte. Asdesired, the method/system irradiates adipose tissue (to augment orsuppress biochemical processes such as Lipolysis) with energy from lightemitting diodes (LEDs) or other suitable light sources, at the effectivewavelength bands or ranges (preferentially absorbed by chromophores inthe adipocytes) in the near infrared (NIR) range. Preferably, the NIRranges are those such that the ratio of the scattering coefficient ofthe photons on human skin (μs) to the absorption coefficient in humanskin (μa) or (μs/μa), is at least a value of about 40. Such nearinfrared radiation may be in wavelength bands between about 850 nm andabout 879 nm and about 900 nm and about 940 nm, and may be deliveredwith a Power Density (W/cm²), temporal characteristics, and/or energydensity (fluence or J/cm²) sufficient to modulate desired pre-initiatedadipocyte biochemical processes.

In one embodiment, this may occur in the absence of any substantial heatrise of greater than about 5 degrees Celsius. Also, as desired, themethod/system will irradiate adipose tissue (to augment or suppressbiochemical processes such as Lipogenesis, Leptin secretion, and glucoseabsorption) with energy from Light Emitting Diodes or other suitablelight source, at the given wavelength bands stated above. The methodsand system of this disclosure may be used to modulate (up-regulate ordown-regulate) one or more of the biochemical processes of Lipolysis,Lipogenesis, Leptin Secretion, and Glucose absorption in the adipocytewhich could lead to the reversal of negative physiological effects suchas obesity and c-reactive protein.

Further summarizing the disclosure, various embodiments may beimplemented for a method and system for irradiating adipose tissue toeffect modulation of biochemical processes within the adipocyte.

DEFINITIONS OF TERMS USED

Throughout the specification and claims, including the detaileddescription below, the following definitions apply.

It should be noted that, as used in this specification and the appendedclaims, the singular forms “a,” “an,” and “the” include plural referentsunless the content clearly dictates otherwise. It should also be notedthat the term “or” is generally employed in its sense including “and/or”unless the content clearly dictates otherwise.

Other than in the operating examples, or where otherwise indicated, allnumbers expressing quantities used in the specification and claims areto be understood as being modified in all instances by the term “about.”Accordingly, unless indicated to the contrary, the numerical parametersset forth in the present specification and attached claims areapproximations that may vary depending upon the desired propertiessought to be obtained by the present invention. At the very least, andnot as an attempt to limit the application of the doctrine ofequivalents to the scope of the claims, each numerical parameter shouldbe construed in light of the number of reported significant digits andby applying ordinary rounding techniques.

Notwithstanding that the numerical ranges and parameters setting forththe broad scope of the invention are approximations, the numericalvalues set forth in the specific examples are reported as precisely aspossible. Any numerical value, however, inherently contains certainerrors necessarily resulting from the standard deviation found in theirrespective testing measurements.

The term “absorbance” as used herein refers to an index of the lightabsorbed by a medium compared to the light transmitted through it.Numerically, it may be represented by the logarithm of the ratio ofincident spectral irradiance to the transmitted spectral irradiance.

The term “dosimetry” as used herein refers to a common, but looselyused, term for energy and/or power density at or across a particularsurface or area. The term can be applied to energy and/or power absorbedwithin the medium of interest. Shortened terms for energy density may beexpressed in Joules or milli-Joules per square centimeter, i.e., J/cm²or mJ/cm². Shortened terms for power density may be expressed in Wattsor milli-Watts per square centimeter, i.e., W/cm² or mW/cm².

The term “energy density” or “fluence” as used herein refers to radiantenergy arriving at a surface per unit area, usually expressed in joulesor milli-Joules per square centimeter (J/cm² or mJ/cm²). It is thetime-integral of irradiance. Terms applied in similar technologiesinclude “radiant exposure,” “light dose,” and “total effective dosage”.

The term “temporal characteristics” as used herein refers to timecharacteristics of the NIR energy used, and can refer to any one or moreof the following terms: pulse width (e.g., in terms of FWHM or 1/epower) of individual pulses, pulse repetition frequency, duty cycle forpulsed applications, and time of application of pulsed or continuouswave (CW) energy.

The term “effective dosimetry” as used herein denotes optical radiationtreatments with near infrared radiation, according to the disclosure, atpower density and energy density (fluence) effective to achieve theresult sought. Furthermore, one of skill will appreciate that theeffective amount of the dosimetry of the invention may be lowered orincreased by fine tuning and/or by applying more than one suitable lightsource or by using the LDOAM radiation of the disclosure with anothermethod of reducing fat known in the art. Further, the angular divergence(e.g., in orthogonal directions to a propagation axis) of the light usedmay be selected or modified as desired, for example by use of one ormore collimating lenses. Although other light sources or lasers may havebeen known and used in removal or reduction of fat, the field hasgenerally remained silent towards the use of a suitable light source atselected wavelengths to initiate, modulate and/or inhibit the innate andoccurring enzymatic processes of adipocytes.

The term “article of clothing” or “item of clothing” as used hereinrefers to any type of clothing such as, but not limited to, a belt, awrap, a bandage, pants, shorts, belt, wrap, arm band, leg band, a shirt,underwear, outerwear, and any item of clothing and apparel that can beused to implement the general idea of the present disclosure.

The term “light skin” as used herein denotes a person who has a skintype between 1 to 4 on a Fitzpatrick scale for skin type.

The term “fat lowering drug” as used herein refers to any natural orsynthetic composition that helps clearing fatty acid and cholesterolfrom the serum.

The term “moderate aerobic exercise” as used herein refers to any typeof activity that increase the hart rate by 20% or more.

The term “immediately following” as used herein denotes the time within½ hour; preferably, within 0-20 minutes; or more preferably, within 5-15minutes.

Conditions that can Affect the Rate of Innate Enzymatic Reactions inAdipocytes

In general, the conditions that can potentially affect the rate ofenzymatic reactions in Adipocytes are:

1) Substrate concentration changes

2) Enzyme concentration changes

3) Temperature changes

4) Hormonal changes.

Substrate Concentration

At lower concentrations, the active sites on most enzyme molecules areless than optimally filled because there is not much substrate withinproximity of the enzyme. Higher concentrations of substrate will causemore collisions between the substrate and enzyme molecules. With moremolecules and collisions, enzymes are statistically more likely to comeupon molecules of reactant (substrate). Within adipocyte cells, thesubstrate for the enzymatic reaction of lipolysis makes up about 97% ofthe volume of the cell. The maximum velocity of a reaction is reachedwhen the active sites of specific enzymes are almost continuously filledwith substrate. Therefore, other ways may preferably be used modulatethe enzymatic rate of necessary and beneficial reactions like lipolysis,by adding specific wavelengths of (free) energy to the cell membrane ofthe adipocyte, where many of the important rate-limiting enzymes forlipolysis lay.

Temperature

A higher temperature will generally cause increased collisions amongmolecules and therefore, increases the rate of an enzymatic reaction.This is normally true because more collisions increase the likelihoodthat substrate will collide with the active site of the enzyme, thusincreasing the rate of an enzyme-catalyzed reaction. However, in thebiological system of adipocyte, increased temperature (by even 3 or 4degrees Centigrade) actually inhibits the reaction rate of lipolysis.

Although other light sources and lasers for the heat-destruction,photo-thermolysis, and/or poration of subcutaneous fat are available,the light sources and lasers used with such procedures have generallyfunctioned at conditions that cannot irradiate areas of tissue greaterthan a couple of cm², and cannot be used or operated independent of atrained physician or technician while an individual is exercising. Theextreme heat generated by these previous methods usually results indegeneration and destruction of any protein and enzymes withinadipocytes and often causes injuries to skin or dermis (with largeamount of water and collagen absorbing the radiation energy) above theadipose tissues.

The present disclosure provides a method and device to gently modulatethe enzymatic rate of necessary and beneficial reactions like lipolysis,by adding specific wavelength and dosimetry free energy to the adipocytemembrane where many of the important rate-limiting enzymes for liplysislay, without significantly increasing the muscle, fat, or coretemperature of the individual. This is accomplished, in accordance withthe disclosure, with Low Dosimetry Optical Adipocte Modulation (LDOAM)techniques implemented in suitable methods and devices as describedherein.

In accordance with embodiments of the present disclosure, LDOAM methodand devices are used to irradiate adipose tissue (to augment or suppressalready occurring biochemical and enzymatic processes such as lipolysisand lypogenesis, respectively) with energy from light emitting diodes orother suitable light sources, at the effective wavelength bands(preferentially absorbed by chromophores in the adipocyte cell membranesand adipocyte mitochondrial membranes) in the near infrared range, wherethe ratio of the scattering coefficient of the infrared photons on humanskin (μs) to the absorption coefficient in human skin (μa) or (μs/μa),is at least a value of 40. In exemplary embodiments, such near infraredwavelengths are in bands between about 850 nm to about 879 nm and about900 nm to about 940 nm; discrete wavelengths may also be utilized, e.g.,at 870 nm and 930 nm. Such energy can be delivered with a Power Density(W/cm²), temporal characteristics, and Energy Density (J/cm²) sufficientto modulate desired—innate and already occurring—adipocyte biochemicalenzymatic processes. This occurs in the absence of any substantial heatrise of greater than about 5° C.

In accordance with exemplary embodiments of the disclosure, the LDOAMdosimetry provides an energy density from about 10 J/cm² to about 10,000J/cm² and a power density from about 0.015 W/cm² to 1 W/cm². Inaccordance with yet another embodiment of the disclosure, the providedenergy density is from about 50 J/cm² to about 8,000 J/cm²; oralternatively, it is from about 100 J/cm² to about 5,000 J/cm². Othersuitable energy densities may be used.

In accordance with one embodiment of the disclosure, the opticalradiation is applied for about 10 to about 120 minutes; preferably, forabout 15 to about 100 minutes; still more preferably, for about 20 to 80minutes. Other application times may also be used within the scope ofthe present disclosure.

The LDOAM methods and devices of the invention can be used to irradiateadipose tissue to augment or suppress biochemical processes such aslipolysis, lipogenesis, leptin secretion, and/or glucose absorption withenergy from one or more light emitting diodes or other suitable lightsource, e.g., suitable laser diodes, at the wavelength bands statedabove. Suitable lights sources and methods of generating suitable NIRlight can include so-called optical parametric devices, e.g., opticalparametric oscillators (OPOs), optical parametric generators (OPGs),optical parametric amplifiers (OPAs), utilizing suitable nonlinearmaterials to produce (e.g., through frequency shifting) desired NIRlight for the LDOAM techniques described herein. The methods and devicesof the present disclosure contemplate modulating (up-regulating ordown-regulating) one or more of the already occurring biochemicalprocesses of lipolysis, lipogenesis, leptin secretion, and/or glucoseabsorption in adipocytes.

Lipolysis

Lipolysis is the biochemical breakdown and release of stored fat fromadipose tissue. This process normally prevails over lipogenesis whenadditional energy is a requirement for the person's activities.Triacylglycerol (fat) within the adipocyte is acted upon by amulti-enzyme complex called hormone sensitive lipase (HSL), whichhydrolyzes the Triacylglycerol into non-esterified fatty acids (NEFA)and glycerol. The regulation of HSL activity is an important factor inthe regulation of biochemical lipolysis and hence the (distal)mobilization of lipids from adipocytes.

Once triglycerides are hydrolyzed to fatty acids and glycerol, fattyacids enter the common free fatty acid pool where they may bere-esterified, undergo beta-oxidation (metabolic degradation), or bereleased into the circulation as substrates for skeletal muscle, cardiacmuscle, and liver. If the fatty acids are to undergo beta-oxidation forATP production, fatty acids move from the adipocytes into the bloodstream and are carried to the tissues that can use them as an energysource.

NEFAs are a significant source of energy (fuel) for metabolic oxidationby working muscle tissue, and the process is normally regulated viahormones during periods of excess energy expenditure, such as exercise.

Generally, entities that participate in a series of intricate enzymaticsteps that modulate lipolysis, as shown in FIG. 1, are adrenergichormonal binding receptors; adenylate cyclase (AC); stimulatory guaninenucleotide binding protein (Gs); inhibitory guanine nucleotide bindingprotein (Gi); cyclic adenosine monophosphate (cAMP); cAMP—dependentprotein kinase; hormone sensitive lipase (HSL); monoacylglycerol lipase;triacylglycerol (TG); glycerol; and non-esterified fatty acids (NEFA).One embodiment of the present disclosure contemplates augmentinglipolysis by affecting any of the entities participating in thelipolysis pathway. The methods of the present disclosure may also affectsystemic and local controls of enzymatic modulation over biochemicalhydrolysis (lipolysis) or synthesis (lipogenesis) of triacylglycerol.

Lipogenesis

Lipogenesis is a collective name for the complex process of producingtriglycerides or fat from smaller precursor molecules such as glucoseand free fatty acids. As shown in FIG. 2, lipogenesis and lipolysis bothoccur in human adipocytes. Modulation of lipogenesis—inhibiting fattyacid synthesis in the adipocyte—may be affected by selectivelyinhibiting glucose uptake in the adipocyte during this period of time,independent of a drug added to the system. In one embodiment of thedisclosure, the regulation of glucose absorption by adipocytes over alarge subcutaneous area, i.e., midriff, thighs, buttocks and arms can bemodulated with near infrared wavelengths bands, one being between about850 nm to about 879 nm and/or the other being about 900 nm to about 940nm, delivered with a Power Density (W/cm²), temporal characteristics,and Energy Density (J/cm²) sufficient to hamper the adipocytebiochemical processes involved in lipogenesis. This can be accomplishedover large subcutaneous areas with Low Dosimetry Optical AdiposeModulation (LDOAM) techniques as described herein. The disclosurefurther contemplates either systemic or local suppression of lipogenesisby modulating any of the related enzymes, as shown in FIG. 2, involvedin that pathway.

Leptin

Leptin is widely reported to have a role in the biochemical regulationof rodent appetite and energy expenditure. The hormone Leptin isreleased by fat cells, as the cells increase in size (lipogenesis) as adirect result of calorie intake. It is also known that circulatingLeptin (an appetite suppressor) signals the hypothalamic areas involvedwith appetite and metabolic rate. It has also been widely reported thatcirculating levels of Leptin are closely and positively correlated withbody fat in humans. In fact, current evidence suggests that multiplefactors including Leptin levels both in the brain and periphery may beinvolved in weight loss and metabolism. The LDOAM method and device ofthe present disclosure modulate Leptin biochemistry of adipocytes tofacilitate fat reduction. According to an embodiment of the disclosure,near infrared wavelengths in bands between about 850 nm to about 879 nmand/or about 900 nm to about 940 nm, with sufficient Power Density(W/cm²), temporal characteristics, and Energy Density (fluence or J/cm²)increase the amount of Leptin normally produced by the adipocytes forpotential use in weight loss and fat regulation.

It has been known that exercise decreases plasma leptin withoutaffecting the gene expression level in adipose tissue in humans. Also,others have shown that in humans, isoproterenol (iniated lipolysis)acutely suppresses leptin levels independently of increased FFAs, andelevated FFAs have no acute effect on leptin levels. However, accordingto in vitro experimentation results with the current disclosure, nearinfrared wavelengths in bands between about 900 nm to about 940 nm, withsufficient Power Density (W/cm²), temporal characteristics, and EnergyDensity (fluence or J/cm²) actually re-coupled the leptin releaseprocess to isoproterenol induced lipolysis, and increased the amount ofLeptin normally produced by the adipocytes during lipolysis. It has alsobeen known that leptin induces a secondary form of lipolysis inadipocytes.

Mechanistically, without wishing to be bound by any theory and notintending to limit any aspect of the disclosure by any theory as to theunderlying mechanisms responsible for the phenomena observed, LDOAMradiation used in the present disclosure induces a lowering of lipolyticenzymatic transition states in lipolytic enzymatic reactions andbeneficially alters the normal cell thermodynamics at the membranelevel, and potentially up-regulates cellular enzymatic processes. Inother words, LDOAM affects molecules that mediate cellularmechano-transduction including, but not limited to, the lipid bilayer ofthe plasma membrane, the extra cellular membrane (ECM), transmembrane“integrin receptors”, and cytoskeletal structures. Even if thismodulation occurs by a small amount, the resulting physical force on themembrane could significantly alter cellular function and to a greaterextent tissue mechanics. This is accomplished without generatingsubstantial heat effects, and is a significant improvement over thebackground art, that simply relies on the effects of heat from a laseror other light source.

In contrast to LDOAM, other optical energies that have considerably lessof a ratio of (μs/μa) than about 40 in the skin (dermis) above theadipose tissue, are less than optimal for absorption by fat cells and/orin modulating cellular mechano-transduction mediators. These wavelengths(because of less than optimal μs/μa ratios) will generally lead toenergy absorption in the dermis above the adipose tissues, and can heatthese dermal tissues to a point that is injurious to the skin, and/or,via absorption, prevent the energy from getting to the subcutaneousadipose tissue.

Human Skin

Human skin is primarily made up of water and collagen. Collagen accountsfor approximately 25% of all protein in humans, and it provides about75% of the dry weight and about 18-30% of the volume of the dermis,which itself constitutes about 15-20% of the weight of the human body.

At many different laser wavelengths, only a single tissue constituent(e.g., water or collagen) absorbs incident radiation. Therefore,understanding the spatial characteristics of the collagen and water“spheres of influence” within dermal tissue is fundamental tounderstanding optical energy-transfer mechanisms through the dermallayer, and to the subcutaneous adipose tissue. In fact, because of thesespatial characteristics of collagen and water within dermal tissue, theactual distribution of optical energy that penetrates the dermis to thesubcutaneous fat may be controlled by more than one influence, the mostimportant influences being:

1) the incident radiant exposure;2) the optical absorption and scattering properties of the tissueitself; and3) the “spot size” (or beam waist diameter, e.g., expressed in terms offull-width have maximum or 1/e powers) of the incident beam.

All three parameters are important to determine energy penetrationthrough the skin to the subcutaneous fat, as are the absorptivechromophores of collagen and water. When one is dealing with biomedicalTissue Optics, tissue absorption coefficients may be used to express theoptical absorption properties of a given tissue element, and may bedesignated as pa. The optical absorption properties of the skin aredominated by the absorption of proteins (collagen), melanin, hemoglobin,and water.

Nevertheless, as shown in FIG. 3, there may be significant differencesin individual chromophores (absorptive elements) within a tissue. Hence,it is postulated that the absorption coefficient of the tissue throughwhich the radiation is traveling is an important factor in determiningenergy penetration through the skin to the subcutaneous fat.

Both optical absorption and scattering play significant roles indetermining the optical spatial distribution of energy density depositedby a radiation source to subcutaneous adipose tissue. If the scatteringcomponent of the equation is negligible or absent (i.e., fat or waterwas being irradiated alone), the optical penetration depth of theincident radiation (the reciprocal of the absorption coefficient) woulditself define the depth to which a given tissue was irradiated andheated.

However, at wavelengths where optical scattering in overlying tissues issignificant, the optical penetration depth may be smaller than thereciprocal of the absorption coefficient, and also may be dependent onthe diameter of the beam spot size. Optical scattering in tissue maytake place because of the spatial differences in the refractive indexwithin tissue. These differences may be dependent on factors thatinclude, but are not limited to: the composition, size, and morphologyof both cellular and extracellular tissue components. Becausecollagen-based tissues like the skin possess vast amounts of collagenfibrils that have significant variability in diameter (30-300 nm),orientation, and spacing, considerable optical scattering occurs.

Therefore, the scale and degree of optical absorption in the skinrelative to optical scattering in the skin (defined by wavelength) is akey value used to determine the spatial distribution of radiationgenerated by the light source that will translate into a safe fluence toselectively irradiate subcutaneous adipose tissues and potentiallyaugment and/or suppress a cell's existing biochemical processes.

If absorption is dominant over scattering in a tissue, the applicationof the Beer-Lambert law is appropriate to determine the spatialdistribution of the absorbed radiation in a tissue from a knownabsorption coefficient of a particular wavelength. However, whenscattering is the prevailing phenomenon, or scattering is equivalent toa wavelength's optical absorption in a tissue, a more detailed model ofradiative transport such as those including Monte Carlo effect analysismay be used to obtain the desired distributions of the absorbedradiation of particular wavelengths.

Because subcutaneous fat begins at a depth of approximately 4 mm orgreater into a patient's skin, and may be deeper for some individuals orsome body areas, the following logic for choosing the correct wavelengthis applied:

-   -   (1) far greater energy is needed (Power density and Energy        Density) for the radiation to be transmitted to the subcutaneous        fat causing selective heating or destruction at the mid-infrared        peaks of 1150 nm and 1230 nm; and (2) the μs/μa ratio are 20 and        8, respectively for these wavelengths and will be more heavily        absorbed in the skin. See FIG. 4.

Therefore a ratio of μs/μa of at least about 40, as shown in FIG. 4, isdesirable for the energy to be able to pass through several millimetersof tissue formed primarily of collagen and water, i.e., the skin (theμs/μa ratio of at least 40 primarily applies to light skins and may notnecessarily work optimally for dark skin, i.e., darker than Fitzpatricktype 4 skin). Consequently, wavelengths in the bands of about 850 nm toabout 879 nm and about 900 nm to about 939 nm (μs/μa approx=60 to 70)may be optimal as they are also absorbed in necessary chromophores (toeffect biochemical modulation of existing enzymatic processes) withinthe adipocyte, without having undesirable thermal consequences in theskin.

When these wavelengths are coupled to a beam spot area of about 1.13 cm²or larger, they may also make use of the phenomena of Monte Carloeffects, to achieve optical tissue penetration through the skin and intothe adipose tissue with less energy than is necessary to significantlyheat up the system. This approach (μs/μa approx=60 to 70, Low Dosimetry(non-thermal), and Large irradiation area greater than 2 cm²) may beused to penetrate the dermal layer and allow absorption of enoughoptical energy at the selected wavelengths in the adipose tissue, andmore specifically adipocyte membrane, to effect Low Dosimetry OpticalAdipose Modulation or LDOAM with minimal heat deposition. This may beaccomplished on large areas of dermal tissue above subcutaneous adiposetissue with Power Densities (W/cm²) and Energy Densities (J/cm²) thatwill not significantly heat up the system being irradiated by more thanabout 5 degrees Celsius in the adipocytes and/or the adipose tissue.

A significant parameter for successful adipose treatment with thepresent disclosure is the internal fluence distribution (exposure) inthe adipose tissue being irradiated with about 930 nm or about 870 nm,which is made possible by the favorable μs/μa ratio in the overlyingskin, and the large irradiation spot size. According to the LDOAMtechniques of the present disclosure, Monte Carlo tissue simulationswith near infrared energy forecast that as an irradiation spot sizebecomes “broad-beam” (1.2 cm or larger equivalent to an area of 1.13cm²), and if the energy profile is a flat field (top-hat effect vsGaussian), the optical energy will achieve a higher fluence distributionin the adipose tissue with the formula, than would be achieved with anirradiation spot of less than 1.2 cm, on the overlying skin.

During a treatment with a LDOAM device, in accordance with the presentdisclosure, the area of tissue to be treated is defined not simply asthe tissue under the optimal beam, i.e., (pi×(radius)²), but as thetreatment volume, i.e., (pi×(radius)²×depth), of the adipose tissue,because the fluence (Energy Density) in the adipose tissue is actuallyincreased with the larger spot sizes and surface areas of irradiation.

As shown in FIG. 5, and according to the present disclosure, the outputpower of the LED array will be of a level such that the Power Density(W/cm²) of the Incident collimated spot will be of a large enough size(generated for example with a short focal length aspheric lens) to causethe distribution of optical energy that penetrates the dermis to be ofgreater fluence at the depth of the adipose tissue than it is at thesurface of the skin. FIG. 5 illustrates an array of LEDs 502 assembledbehind an aspheric lens 504 generating a collimating beam 506 withvarious diameters. Each LED consists of an LED assembly 508 connected toa power conduit by pins 510 and 512. Aspheric lens 504 is designed torefract light at large angels without introducing any significantspherical aberrations. It can have much shorter focal lengths than acomparably sized spherical lens. Because an aspheric surface minimizesthe aberrations experienced by rays traveling through the outercircumference of a lens, it is specially useful for short focal lengthapplications. Aspheric lens 504 may have a desired shape (e.g.,elliptical, parabolic, hyperbolic, etc.) and/or optical prescription.Accordingly, aspheric lens 504 may be used to modify or control outputintensity from the light source(s) to conform to a desired intensitydistribution, e.g., a top-hat distribution, at a target site. In doingso, collimating lens 504 can accommodate or correct angular divergencedisparities (aspect ratios) in the optical output of the light sourcesused, e.g., LEDs 502. In certain embodiments, (e.g., as shown in FIG. 6)arrays of suitable light sources (with or without collimating lenses)may be used in conjunction with (e.g., embedded, attached to, or placedin, etc.) a wrap or bandage that is conformable to a desired targetsurface, e.g., such a portion of a person's body. Accordingly, LDOAMradiation at LDOAM dosimetries can be applied to a person to treat(e.g., modulate biological processes in) adipose tissue.

This Fluence (Energy Density) distribution to the adipose tissue underthe skin can therefore be maintained with less energy and power whileavoiding any significant thermal rise in the area. Hence, safe andpractical adipose biochemical modulation can occur with theseaccomplished parameters. The methods and device of the disclosureprovide that:

-   -   1) The internal fluence distribution to the adipose tissue is        greater than the surface fluence to the skin;    -   2) The illumination zone of treated adipose tissue given by        (pi×(radius)²×depth) will be generated by large collimated        irradiation spots to make use of known Monte Carlo effects of        Optical Energy Tissue distribution phenomena; and    -   3) With larger spot sizes, the treatment area (adipose tissue)        is defined by the area of tissue volume under the beam where the        fluence (Energy Density) is higher than the incident (surface)        Energy density, via Monte Carlo forecasts and calculations.

The graph shown in FIG. 7, represents the effect on illumination zonefluence and tissue volume that is generated by optical spot size. Datais represented by Monte Carlo iso-fluence lines. Here, it can be furtherseen, that where treatment would begin at 12 mm spot sizes up to atheoretical “infinite spot size,” that a spot of about 1.2 cm producestissue fluence (deeper in the treatment zone) at approximately 75% thatof the theoretical infinite spot size.

In contrast, the smaller spot sizes available with conventional fibersand optics, such as lasers, must increase fluence substantially greaterthan that generated by the present disclosure to produce adequate tissuepenetration to the depth of the adipose tissue, and would thermolyzeand/or burn tissue or porate adipocyte membranes, an effect that is notdesirable.

The LDOAM techniques according to the present disclosure can provideradiation dosages at predetermined power densities and exposure timesthat thermodynamically lower enzymatic transition states of necessaryenzymes in the adipocyte, via the absorption of optical energy at aselected wavelength of about 850 to about 879 nm, preferably about 870nm and/or about 900 to about 940 nm, preferably about 930 nm in thelipid bilayer, and in the lipid pool, hence altering and modulatingvital biochemical pathways in these cells. This is occur during periodsof sport or exercise and is desired to facilitate adipocyte reductionand shrinkage.

The LDOAM treatment parameters are specified in terms of the averagesingle or additive output power (milli-Watts) of the LED array, afiltered incandescent lamp, or other suitable light sources, atwavelengths of about 870 nm and about 930 nm. This information, combinedwith the area of the irradiation at the treatment surface beingselected, will govern the calculations for effective radiation dosimetryand safe treatment of a given area and volume of tissue or cells.

For all laser stimulatory effects, the dosimetry used in the presentLDOAM method and device is significantly less than that used tooptically harm mammalian and/or bacterial cells, but enough to targetand stimulate the previously discussed molecular endogenous LDOAMtargets (e.g., cell membranes, lipid pool) in mammalian adipocyte cellsin a beneficial fashion to enhance a given desired therapy.

According to one aspect of the present disclosure, the therapeuticsystem includes an optical radiation generation device adapted togenerate LDOAM optical radiation, a delivery assembly for causing saidoptical radiation to be transmitted through an application region, and acontroller operatively connected to the optical radiation generationdevice for controlling the dosage of the radiation transmitted throughthe application region, such that the time integral of the power densityof the transmitted radiation per unit area is below a predeterminedthreshold.

According to one embodiment of this aspect of the disclosure, the LDOAMoptical radiation generation device may further be configured togenerate optical radiation substantially in either or both LDOAMwavelengths (about 850 to about 879 nm, preferably about 870 nm and/orabout 900 to about 940 nm, preferably about 930 nm). The therapeuticsystem may further include a delivery system for transmitting theoptical radiation in the second wavelength range through an applicationregion and a controller operatively for controlling the opticalradiation generation device to selectively generate radiationsubstantially in the first wavelength range or substantially in thesecond wavelength range or combinations thereof.

According to a further embodiment, the controller of the therapeuticsystem includes a power limiter to control the dosage of the radiation.The controller may further include memory for storing patients' profileand a dosimetry calculator for calculating the dosage needed for aparticular patient based on the information input by a physician.

The optical radiation can be delivered from the therapeutic system tothe application site in different patterns, such as, for example, in asingle wavelength pattern or in a dual-wavelength pattern in which twowavelength radiation are multiplexed or transmitted simultaneously tothe same treatment site. Alternatively, the radiation can be deliveredin an alternating pattern, in which the radiations in two wavelengthsare alternatively delivered to the same treatment site. The interval canbe one or more pulses.

By employing a dual wavelength LDOAM method and device, the wavelengthsare extraordinarily selective substantially at about 870 nm and about930 nm, and are used at significantly lower energy levels than areneeded to raise membrane temperatures to the point of causing damage tothe membrane of the healthy adipose cells.

With the therapeutic methods, device, and system according to thepresent disclosure, unwanted thermal injury to healthy tissue can beprevented in the site being irradiated (undesired adipose tissue) bymaintaining the radiance (joules/cm²) and/or exposure time to a limit ofdefined parameters. These defined parameters are easily programmed intoa control system by way of a programmed dosimetry calculator included inthe system.

The LDOAM method and device and system of the present disclosure may, inaddition to augmenting and suppressing biochemical lipolysis andlipogenesis, respectively (as shown in FIGS. 1, 2, and 8) and increasingLeptin production, have one or more of the following whole body effects:

a) reduction of whole body insulin resistance, thereby

b) decreasing diabetes mellitus,

c) decreasing hypertriglyceridemia,

d) decreasing levels of high-density lipoprotein cholesterol,

e) increasing levels of low-density lipoprotein cholesterol,

f) increasing levels of adiponectin,

g) decreasing C-reactive protein,

h) decreasing interleukin-6, and

i) decreasing tumor necrosis factor (alpha).

As shown in FIG. 9, the present device can be incorporated into or on anoptical energy dispersion belt, bandage, or wrap, for example, for useas an adjunctive treatment of subcutaneous adipose opticalbio-regulation to allow for large areas to be simultaneously treatedwith controlled optical dosimetry. Such an optical energy dispersionbelt or bandage or wrap can be fabricated with multiple arrays of LEDsoperative at the desired wavelength(s). In accordance with the presentdisclosure, each array can be collimated with a collimating lens of ashort focal length (in one adaptation this would be an asphericcollimating lens, as seen in FIG. 6). This allows large areas ofsubcutaneous adipose tissue to be treated simultaneously during suchactivities as exercise, making use of Monte Carlo phenomena (i.e., largespot sizes) that modulate existing biochemical lipolysis andlipogenesis. Such collimating lenses can be configured and arranged asdesired and may be used to produce a desired (e.g., flat top) intensitydistribution, and may account for any beam output aspect ratio of thediodes used, which often have dissimilar angular divergence betweenorthogonal axes of beam output.

The present disclosure provides a method, device, and a system forreducing the level of fat or lipid in an adipocyte without significantgeneration of heat or intolerable adverse effects on the skin. In oneembodiment, the method of the disclosure comprises the step ofirradiating a target site with a first optical radiation having awavelength band from about 905 nm to about 945 nm and/or a secondoptical radiation having a wavelength band from about 850 nm to about879 nm at a dosimetry from about 0.015 W/cm² to 1 W/cm², to modulateinnate biochemical processes of adipocytes in the target site.Preferably, the first wavelength band of the optical radiation rangesfrom about 925 to about 935. In accordance with one embodiment of thedisclosure, each of wavelength bands may be irradiated alone or incombination with the other band, sequentially or in tandem. Preferably,the radiation bands are collimated when an incoherent light source isused to generate the above-mentioned wavebands.

In yet another embodiment of the disclosure, the biochemical processesmodulated by the LDOAM dosimetry include, but are not limited to,lipolysis, lipogenesis, leptin production, and glucose absorption ormetabolism. Preferably, these processes already are in progress, whenLDOAM is used, either by sport and exercise activities or digestion andpharmacological means.

In another embodiment of the disclosure, LDOAM radiation is generated bylight emitting diode (LED) arrays or by super-luminous LED arrays.Preferably, LEDs are arrayed with aspheric collimating lenses within awrap.

The present disclosure further provides a device comprising a suitableoptical light source such as LED arrays for generating LDOAM. In anembodiment, LED arrays with aspheric collimating lenses are assembledwithin an article of clothing. In yet another embodiment, such articleof clothing has means for attaching to a power source and can be worn bya person while using a sport or exercise equipment to facilitate fatreduction.

According to a further aspect of the invention, an optical energydispersion system for use as an adjunctive treatment of for subcutaneousadipose optical bio-regulation is provided, which allows for large areasto be simultaneously treated with controlled optical LDOAM wavelengthsand dosimetry generated from multiple light emitting diode arrays(LEDs). See FIGS. 5 and 9. FIGS. 10A-E illustrate several embodiments ofthis aspect of the disclosure.

According to another embodiment of this aspect of the disclosure, thereis provided an optical energy dispersion belt, bandage, or article ofclothing for use as a treatment to enhance the efficiency of aerobicexercise, by augmenting lipolysis at the earliest possible point inmoderate aerobic exercise, to allow for non-esterified fatty acid(NEFA's) to enter the blood stream to be used as metabolic fuel moreefficiently than would occur without the disclosure. This would alsomaintain a high level of subcutaneous adipose lipolysis to aid in thepreferential use of NEFA's for metabolic fuel. See FIGS. 10A-E.

Other Exemplary LDOAM Embodiments

About 90 minutes after a person finishes a meal, (i.e., thepost-absorptive state) glucose metabolism in the individual willapproach a steady state, where approximately 80% of all blood glucosewill be taken up by various tissues. In this state, approximately 50% ofthe glucose is taken up by the brain, and 20% is absorbed by the redblood cells. As a general rule, muscle and adipose tissue together onlyabsorb the remaining 20% of total glucose utilization.

Enzymatic Activation Energy

It is shown, for example, in the graph in FIG. 11, that if theactivation barrier to a biochemical reaction (such as lipolysis) can belowered through the use of the present disclosure. The addition of freeenergy (at defined wavelengths and dosimetries) may prospectively causethe necessary reactants to have a greater potential energy (vibration).This allows these reactants to more easily position themselves in theenzymes active sites in the membranes, for the enzymatic reaction oflipolysis. This can occur by making the formation of an enzyme mediatedtransition state more frequent, thus decreasing the activation energy ofthe reaction, and causing a faster reaction rate.

Many of the complex enzymes associated with the plasma membrane of theadipocyte are tightly bound to it in a variety of ways. Transmembraneproteins have their polypeptide chains passing completely through thelipid bilayer. In the midst of the membrane (lipid bilayer) associatedproteins, the segments of the proteins within direct proximity of thelipid bilayer consist primarily of hydrophobic amino acids. Thesespecific proteins are usually arranged in what is known as an alphahelix, so that the polar —C═O and —NH groups at the peptide bonds caninteract with each other, rather than with their hydrophobicsurroundings. In contrast, the fraction of the proteins that project outfrom the membrane have a predisposition towards elevated percentages ofhydrophilic amino acids.

It is known that the composition of human adipocyte plasma membranes ismainly made out of phosphatidylcholine and phosphatidylethanolamine,with sphingomyelin, phosphatidylserine, and phosphatidylinositol beingless abundant. More importantly, the mean value of the total proteincontent of the adipcyte membranes is reported to be approximately 50% bydry weight.

The present method selectively targets these unique hydrocarbon (lipid)chains of the bilayer of the plasma membranes of adipocytes, and mayalter the static orientational order of the membrane lipid bilayer, withdirectly absorbed (milli-Watt) energy, to optically force changes in themembrane, causing dynamic interactions of the bilayer. This concomitanttransduction then leads to conformational (structural) changes in themembrane bound proteins that catalyze and modulate adipocyte processessuch as lipolysis. These processes can be altered by things likephysical forces on the membrane, minor changes in the extracellularmatrix (ECM) that the eukaryotic cell resides in, and any changes in thebasic cell structure. The molecular mechanism by which a cell senses andresponds to external mechanical stress has been referred to as “cellularmechanotransduction”.

The molecules that mediate cellular mechanotransduction include thelipid bilayer of the plasma membrane, the ECM, transmembrane “integrinreceptors”, and cytoskeletal structures. Therefore, any externalstimulus or device that may cause optical interference with the normalcell membrane thermodynamics (without generating substantial heateffects) and hence cause cellular mechanotransduction to the plasmamembrane and biochemical pathways, is considered novel and animprovement of the prior laser art, that simply relies on the effects ofheat from a laser.

Hence, if the lipid bilayer actively absorbs milli-watt photon energy atabout 870 and/or about 930 nm, for example, causing increased kineticinteractions on a molecular level in the molecular bonds that make upthe membrane (but in the absence of a significant temperature increase)the membrane will appreciate free energy addition and mildmechanotransduction forces that could significantly alter cellularfunction and to a greater extent the adipose organ being irradiated.

Minute mechanical forces can regulate a cells biochemical activity in amanner that is equally as potent as chemical or pharmacological signals.This means that slight deformations in a cell membrane (because of theincreased kinetic energy associated in the lipid bilayer of the cellmembranes with about 870 nm and/or about 930 nm optical absorption) canand will cause remarkable conformational changes to the vitaltrans-membrane proteins. This could be a direct ramification of cellularmechanotransduction via the increased kinetic energy of the C—C and C—Hbonds in the lipid bilayer from 930 nm optical energy absorption.

It is believed that as the lipid hydrocarbon component of cell membranesabsorb the wavelength about 870 and/or about 930 nm infrared energy inthe carbon-hydrogen bonded chains at correct dosimetry to effect change(but below deleterious thermal dosimetry), that kinetically drivenevents could alter the molecular dynamics of membrane-bound proteins(such as trans-membrane Adenylate Cyclase) through significantlyincreased molecular motions of the lipids in the membrane as they absorbenergy from the LDOAM system. Because even a small chemical shift in thelipid bilayer (such as reduced packing constraints or distance betweenthe lipids) could be enough to change the molecular shape of an attachedrespiratory and/or transport protein (along with the thermodynamics andkinetics of the enzyme), and render it more active, the LDOAM system ispotentially a powerful tool for modulation of biochemical processes inadipocytes.

These events are believed to be unique to the LDOAM system, and are notat all reflective of the large infrared bands claimed, or far largerdosimetries needed for thermal interactions revealed in the prior art.

As postulated by the present inventor, and without being bound by anytheory of operation, if the wavelength about 870 nm and/or about 930 nmnear infrared energy is preferentially absorbed by long chain C—Hmolecules, and these long chain C—H molecules are the basis of thephospholipid bilayer of cell membranes, it would take very littlealteration in the local environment of one of these proteins (sittingwithin the membrane) to change its 3-D conformational shape, and hencemodulate or augment its function. If this conformational change occurs,causing/influencing enzymatic action, increased lipolytic activity couldalso occur. The mechanism postulated above has been corroborated to anextent by data presented through the inventors experimental in vitrodesigns, described herein.

The present inventor tested human adipocytes that were plated intoselected wells of 24-well tissue culture plates for selected LDOAMexperiments at given dosimetry parameters. The plates were inoculatedwith isoproterenol immediately before irradiation to initiatebiochemical lipolysis in all treatment and control wells, and theproducts of lipolysis were measured as glycerol and fatty acidconcentrations outside of the cells.

These experiments showed that under specific irradiation protocols withthe 930 nm wavelengths, that there was a significant augmentation ofbiochemical lipolysis (above the non-irradiated controls), without aconcomitant temperature increase of the experimental model, oncelipolysis was initiated with Isoproterenol.

It has been reported in the literature that the maximum lipolyticresponse to isoproterenol is limited by the accumulation of cyclic AMPand, that a plot of log cAMP vs. glycerol release (during lipolysis)results in linear relationship as the level of cAMP rises.

Adenylate Cyclase is the enzyme that catalyzes the formation of cylicAMP from ATP. This enzyme is vitally important in many areas ofEukaryotic Signal Transduction. Adenylate cyclase can be activated orinhibited by the G proteins that are coupled to plasma membranereceptors and are thus able to respond to hormonal or other stimuli.

Therefore, without wishing to be bound by any theory and not intendingto limit any aspect of the disclosure by any theory as to the underlyingmechanisms responsible for the phenomena observed, it is postulated thatthe wavelengths irradiated according to the present methods and systemsare absorbed by the adipocyte cell membranes, and effect thetransmembrane Adenylate Cyclase enzyme, increasing the level ofintracellular cAMP through a mechanism of optically mediatedmechanotransduction, that then upregulates or forward modulates thedistal lipolytic cascade of enzymes to produce more products oflipolysis (Glycerol and FA).

Photochemistry, Photophysics and Phototherapy

The First Law of Photochemistry (and photophysics) states that photonsmust first be absorbed for photochemistry (or photophysics) totranspire. As photobiological and phototherapeutic effects are initiatedby photochemistry (or photophysics), no photochemistry (or photophysics)will occur, unless a particular wavelength of light is absorbed by abiological system. This is true independent of the length of time thatone would irradiate a system with a non-absorbed wavelength of light. Anumber of studies in the prior art have not taken into account this“First Law of Photochemistry (and photophysics) in publishing theresults in the literature.

The absorption spectrum of a given wavelength of light is a plot of theprobability that the photons (of the given wavelength) will be absorbedby the biological system being irradiated. As each chemical compound ina biological system has a different absorption spectrum, because of itsunique electronic structure, every individual wavelength that isabsorbed by a chemical compound will be absorbed to different degrees.

Once a given photobiological response is observed, the next step is todevelop and determine the optimum dose of the wavelength of radiationneeded to produce the desired photobiological effect, and establish whatis called the action spectrum. The action spectrum is a plot of therelative effectiveness of different wavelengths of light (at differentdosimetries) that will cause a particular biological response.Therefore, the action spectrum not only identifies the wavelengths thatwill have the maximum desired biological effect with the least dose ofradiation, but also identifies the molecular target of the radiation.

When a photon of light is absorbed by a molecule, the electrons of thatmolecule are raised to a higher energy state. This (now) excitedmolecule then must lose the extra energy that the photon provided. Withnear-infrared wavelengths, this generally occurs by the vibratingmolecules giving off heat. The Photobiological responses of augmentedlipolysis are the result of photochemical and/or photophysical changesproduced by the absorption of the LDOAM non-ionizing radiation.

The inventor's studies have demonstrated that the degree of thephototherapy effect depends on the physiological state of the adipocytesat the instant of irradiation. For example, when irradiating adipocytesthat were not undergoing lipolysis at Energy Densities from 8 J/cm² to4000 J/cm², the effect of the irradiation on the adipocytes was minimalor nonexistent. In such testing, only after lipolysis was initiated withthe drug Isoproterenol (to mimic moderate exercise) the phototherapeuticeffect of augmented Lipolysis was observed with 10-20 J/cm² irradiationat about 930 nm, and 20.4 J/cm² at about 870 nm.

It has also been shown that there may be no significant differencewhether the light used for Biostimulation and/or phototherapy isgenerated by a laser or from non-coherent light of the same wavelength(i.e., filtered incandescent lamp or LED).

Phototherapy of adipocytes—whether using about 930 nm and/or about 870nm low-intensity radiation in from a laser, an LED, or a filteredincandescent lamp—can potentially be beneficial in a number of clinicalsituations, as an augmentation to exercise and weight-loss.

As was described, about 870 nm and/or about 930 nm energy may beactively absorbed in the molecular bonds of the lipids, in the lipidpool of the adipocyte that in turn causes increased kinetic interactionson a molecular level of the fatty acid substrates for lipolysis. Theseincreased kinetic interactions caused by the absorption of photons ofabout 870 nm and/or about 930 nm may immediately be converted tovibrational and rotational energy within the fatty acid molecules whichis the molecular basis for heat. However, as will be evident with thedosimetric range involved for augmented lipolysis to be achieved withthe LDOAM system, there is not sufficient energy density (Joules/cm²)added to the lipid pool of the adipocyte to raise the temperature by therequired amount to inhibit lipolysis. Also, on the extreme end of thebackground art with other laser wavelengths, photothermolysis (heatinduced death) of adipocytes with near infrared laser energy has beenimplemented with significantly larger energies and temperatureincreases. Much of the prior art desires the destruction of adiposetissue thermally, for its surgical removal, which is not the method orintent of the present disclosure.

Another example of potential Low Level enzymatic stimulation with about870 nm and/or about 930 nm of the adipocyte can occur through thecellular cytoskeleton. In mammalian cells, the cellular organelles,nuclei and most importantly the cell membrane lipid bilayer areinterrelated and organized by a comprehensive series of cytoskeletalfilaments. Many of these are also connected linked with ECM molecules bymeans of specific receptors on the outside of the cell membrane that astransmembrane receptors are still connected to the cytoskeleton. Thebiochemical regulation of a cell's shape and function is mechanicallycontrolled by the structural and functional geometry of these intra- andextra-cellular system in the cytoskeleton of mammalian cells includingadipocytes.

The mammalian cytoskeleton is a highly integrated network of fibers,filaments and polymers all formed within the cell as part of normalfunction. Any mechanical modification of this network of cytoskeletalfibers (such as increase of kinetic energy from absorption of thewavelength about 870 nm and/or about 930 nm optical energy in anadipocyte pool or membrane) can alter the chemical environment of thecell, and potentially induce changes in cell shape, motility andmetabolism, by changing the molecular dynamics of the cell.

The cytoskeleton is actively implicated in a range of cell functionsthat include force transduction and production, cell membranemodulation, hormone secretion, intracellular transport, organelletranslocation, and cell migration. The cytoskeleton serves to provide ameasure of mechanical stiffness to resist cell deformation in the faceof forces like fluid flow dynamics, or mechanical stresses fromsurrounding tissues. Even though it has not been clearly explained howthe physical mechano-transduction and concomitant deformation of a cellmembrane protein or cytoskeletal component can lead to a givenbiochemical response, it has been suggested in many tissues that thisnetwork of filaments, once deformed, will change the membrane tensionforce in cells and alter things like mechano-sensitive ion and nutrientchannels and enzymes.

The molecules that mediate cellular mechano-transduction include thelipid bilayer of the plasma membrane, the ECM, transmembrane “integrinreceptors”, and cytoskeletal structures. Therefore, any optical externalstimulus or device that may induce a lowering of lipolytic enzymatictransition states in lipolytic enzymatic reactions will beneficiallyalter the normal cell thermodynamics at the membrane level, andpotentially up-regulate cellular enzymatic processes.

Ability to Penetrate Beyond the Dermal Layer to Subcutaneous AdiposeTissue

The absorption spectrum of water has a therapeutic transmission windowin the near-infrared until about 940 nm, then a sharp upswing to a peakat 980 nm. See FIG. 12. This allows the wavelength of about 870 nmand/or about 930 nm electromagnetic energy to pass through the dermallayer (about 85% water) and impact the adipose tissue directly under theskin.

Aerobic Exercise

Sub-maximal aerobic exercise is the best technique to maximize lipolysisand reverse obesity. A level from about 20% to about 40% Vo2 Maxexercise intensity will causes a rise in the hormones epinephrine,norepinephrine, and growth hormone to inhibit the release of insulinfrom the pancreas. This hormonal environment enhances liver glucoseoutput and promotes greater fat utilization and lipolysis.

A gradual loss of body fat comes about from burning more calories duringexercise than one takes in through exogenous sources. In view of thefact that mild to moderate aerobic training (about 40% Vo Max) creates ametabolic environment that is advantageous for fat metabolism, there isa need in the art to increase the body's fat-burning proficiency(lipolysis) after initiating that mild to moderate aerobic exercisewithout increasing the negative feedback parameters to the lipolyticreactions, that are the significantly elevated temperature andepinephrine concentrations from intense exercise. Application of thepresent method during or following exercise increases fat metabolism andresults in enhanced weight loss.

Increased Exercise Intensity and Decreased Lipolysis

Endogenous triacylglycerols characterize an important source of fuel forexercise. Lipolysis increases progressively during exercise, with thespecific rate determined by energy requirements of working muscles,monoglyceride delivery to mitochondria in the working muscles, and theoxidation of other substrates such as glycogen. It is the catecholamineresponse to exercise that increases lipolysis in adipose tissue.

Alterations in lipolysis and fatty acid mobilization during exercisedepend, in large part, on exercise intensity and core body temperature.Lipolysis is lower in high-intensity exercise, than inmoderate-intensity exercise, in part because of increase epinephrine andheat in the system. For example, for the duration of exercise at about65% peak pulmonary oxygen uptake (VO₂ peak), an increased coretemperature will lead to increased carbohydrate oxidation duringexercise and a concomitant decrease in lipolysis. This is caused byincreased muscle glycogen use with no change in glucose uptake by themuscle

It is also recognized the epinephrine concentrations are elevated duringexercise in the heat compared with exercise in cooler environments. Ithas been confirmed that a 2-fold increase in circulating adrenalineincreased muscle glycogen utilization, glycolysis and carbohydrateoxidation when subjects were exercising at about 70% peak pulmonaryoxygen uptake (VO2 peak). The magnitude of the increase in adrenaline inthat study was similar to those observed in previous studies thatcompared hot and thermo-neutral environments. Thus the increase in coretemperature during exercise in the heat may also result in an increasedadrenaline secretion.

Without wishing to be bound by any theory and not intending to limit anyaspect of the disclosure by any theory as to the underlying mechanismsresponsible for the phenomena observed, it is postulated that when aphoton of light is absorbed by a molecule, the electrons of thatmolecule are raised to a higher energy state. This (now) excitedmolecule then must lose the extra energy that the photon provided. Withnear-infrared wavelengths, this generally occurs by the vibratingmolecules giving off heat. The Photobiological responses of, forexample, augmented lipolysis are the result of photochemical and/orphotophysical changes produced by the absorption of the LDOAMnon-ionizing near infrared radiation.

EXAMPLES LDOAM Treatment Parameters for In Vitro Adipocyte Tests

The following parameters illustrate the methods according to thedisclosure as applied to Human Adipocytes at thresholds well belowthermal damage. Cultured human adipocytes were obtained from Zen-BioInc., North Carolina and used for in vitro experimentation. Theadipocyte precursor cells (preadipocytes) were isolated fromsubcutaneous adipose tissue from elective surgery in healthynon-diabetic donors between 18 and 60 years old. The preadipocytes wereisolated by centrifugal force after collagenase treatment, and thencultured as growing precursor cells. These cells were thendifferentiated into adipocytes using medium supplemented with adipogenicand lipogenic hormones. The process of differentiating preadipocytes toadipocytes is disclosed in U.S. Pat. No. 6,153,432.

Glycerol Assay

To assess lipolytic activity using the measurement of glycerol releasedinto the medium is the method of choice, as the enzyme glycerokinase (tocreate glycerol fromprecursors) is not present in adipocytes. Glycerolreleased to the medium is phosphorylated by adenosine triphosphate (ATP)forming glycerol-1-phosphate (G-1-P) and adenosine-5′-diphosphate (ADP)in the reaction catalyzed by glycerol kinase. G-1-P is then oxidized byglycerol phosphate oxidase to dihydroxyacetone phosphate (DAP) andhydrogen peroxide (H2O2). A quinoneimine dye is produced by theperoxidase catalyzed coupling of 4-aminoantipyrine (4-AAP) and sodiumN-ethytl-N-(3-sulfopropyl)m-anisidine (ESPA) with H2O2, which shows anabsorbance maximum at about 540 nm. The increase in absorbance at about540 nm is directly proportional to glycerol concentration of the sample.The glycerol assay kit was obtained from Zen-Bio Inc., North Carolina.

Free Fatty Acid Assay

Assessment of lipolytic activity was be detected through measurement ofnon-esterified fatty acids (NEFA) released by adipocytes. Thiscolorimetric assay allows for direct Free Fatty Acidsin the media toform a purple product that absorbs light at about 550 nm. This allowsthe concentration of NEFA to be determined from the optical densitymeasured at about 540 to about 550 nm. The NEFA assay kit was obtainedfrom Zen-Bio Inc., North Carolina.

Leptin Assay

Assessment of Leptin production and secretion from the human adipocyteswas completed with a quantitative sandwich enzyme immunoassay technique.A monoclonal antibody specific for Leptin was pre-coated onto amicroplate, and standards and samples were pipetted into the wells whereany Leptin present was bound by an immobilized antibody. After washingaway any unbound substances, an enzyme-linked monoclonal antibodyspecific for Leptin was added to the wells. Next, following a wash toremove any unbound antibody-enzyme reagent, a substrate solution wasadded to the wells and a color developed in proportion to the amount ofLeptin bound in the initial step. Finally, the color development isstopped and the intensity (optical density) of the color was measured.The Leptin Assay kit was obtained from R&D Systems, Inc., 614 McKinleyPlace N.E. Minneapolis, Minn. 55413.

Cell Cultures for Experiments

All human adipocytes were plated into selected wells of 24-well tissueculture plates for selected NIMEL experiments at given dosimetryparameters. The plates were inoculated with isoproterenol immediatelybefore irradiation to initiate biochemical lipolysis in all treatmentand control wells.

Following Optical Treatments with a NIMEL Laser System, the directionswere followed for the Zen-Bio Glycerol and Fatty Acid Assay kitsdescribed previously Equivalent assay studies and incubation times wereperformed for all NIMEL irradiation tests with Human Adipocyte Cells inthe in vitro tests. Data in set in bold represent actual change fromcontrol (non-irradiated) samples.

Example I Dosimetry Values for Wavelength 870 Nm In Vitro

The NIMEL single wavelength of about 870 nm demonstrates lipolysissuppression in vitro at the following dosimetry ranges.

TABLE I NIMEL BEAM ENERGY POWER OUTPUT SPOT TREAT- DENSITY DENSITY POWER6 CM MENT TOTAL (RADIANT (IRRA- (W) DIAM- TIME ENERGY EXPOSURE) DIANCE)870 NM ETER (SEC) (JOULES) (J/CM²) (W/CM²) Plate 5 28.26 15 min 450 J15.3 J/cm² 0.017 0.5 W cm² 900 sec W/cm² Time After Irradiation Plate(min.) Treated 1 Control 1 Control 2 Glycerol Concentrations Gly Conc.(micro. M) 5 30 35.3846 44.2308 43.4615 5 60 51.9231 62.3077 65.0000Free Fatty Acid Concentrations FFA Conc. (micro. M) 5 30 241.5000294.8333 254.0000 5 60 297.3333 427.3333 449.8333 Relative GlycerolRelative Free Fatty Acid Concentrations Concentrations (Percent ofcontrol) (Percent of control) Time After Time After IrradiationIrradiation Plate (Min.) T1 % Cont Plate (Min.) T1 % Cont 5 30 81.42 530 95.08 5 60 79.88 5 60 66.10

The single wavelength of 870 nm demonstrates Lipolysis augmentation invitro at the following dosimetry ranges.

TABLE I-A NIMEL BEAM ENERGY POWER OUTPUT SPOT TREAT- DENSITY DENSITYPOWER 6 CM MENT TOTAL (RADIANT (IRRA- (W) DIAM- TIME ENERGY EXPOSURE)DIANCE) 870 NM ETER (SEC) (JOULES) (J/CM²) (W/CM²) Plate 5 28.26 20 min600 J 20.4 J/cm² 0.017 0.5 W cm² 1200 sec W/cm² Time After IrradiationPlate (min.) Treated 1 Control 1 Glycerol Concentrations Gly Conc.(micro. M) 5 15 16.1538 5.0000 5 75 30.0000 21.5385 5 135 48.846225.7692 Free Fatty Acid Concentrations FFA Conc. (micro. M) 5 15 49.000019.0000 5 75 159.0000 69.0000 5 135 207.3333 83.1667 Relative GlycerolRelative Free Fatty Acid Concentrations Concentrations (Percent ofcontrol) (Percent of control) Time After Time After IrradiationIrradiation Plate (Min.) T1 % Cont Plate (Min.) T1 % Cont 5 15 323.08 515 257.89 5 75 139.29 5 75 230.43 5 135 189.55 5 135 249.30

Example II Dosimetry Values for Wavelength 930 Nm In Vitro

The single wavelength of about 930 nm demonstrates substantial lipolysisaugmentation in vitro at the following ranges.

TABLE II NIMEL BEAM ENERGY DENSITY OUTPUT SPOT TOTAL (RADIANT POWERDENSITY POWER (W) 6 CM TREATMENT ENERGY EXPOSURE) (IRRADIANCE) 930 NMDIAMETER TIME (SEC) (JOULES) (J/CM²) (W/CM²) Plate 6 28.26 cm2  15 min450 J 15.3 J/cm² 0.017 W/cm² 0.5 W 900 sec Time After Irradiation Plate(min.) Treated 1 Control 1 Control 2 Glycerol Concentrations Gly Conc.(micro. M) 6 30 51.9231 31.5385 46.1538 6 60 81.1538 52.3077 70.7692Free Fatty Acid Concentrations FFA Conc. (micro. M) 6 30 510.6667195.6667 138.1667 6 60 404.0000 254.0000 329.8333 Relative GlycerolRelative Free Fatty Acid Concentrations Concentrations (Percent ofcontrol) (Percent of control) Time After Time After IrradiationIrradiation Plate (Min.) T1 % Cont Plate (Min.) T1 % Cont 6 30 112.50 630 369.60 6 60 114.67 6 60 122.49

The single wavelength of about 930 nm demonstrates substantial Lipolysisaugmentation in vitro at the following ranges.

TABLE II-A NIMEL BEAM ENERGY DENSITY OUTPUT SPOT TOTAL (RADIANT POWERDENSITY POWER (W) 6 CM TREATMENT ENERGY EXPOSURE) (IRRADIANCE) 930 NMDIAMETER TIME (SEC) (JOULES) (J/CM²) (W/CM²) Plate 3 28.26 cm² 20 min600 J 20.4 J/cm² 0.017 W/cm² 0.5 W 1200 sec Time After Irradiation Plate(min.) Treated 1 Control 1 Glycerol Concentrations Gly Conc. (micro. M)3 15 9.2308 3.0769 3 75 21.5385 12.6923 Free Fatty Acid ConcentrationsFFA Conc. (micro. M) 3 15 21.5000 8.1667 3 75 59.8333 49.0000 RelativeFree Fatty Acid Relative Glycerol Concentrations Concentrations (Percentof control) (Percent of control) Time After Time After IrradiationIrradiation Plate (Min.) T1 % Cont Plate (Min.) T1 % Cont 3 15 300.00 315 263.27 3 75 169.70 3 75 122.11

Example III Dosimetry Values for Wavelengths 870 and 930 Nm In Vitro

The Simultaneous wavelengths of 870 nm and 930 nm demonstrates littlechange from the control in the rate of Lipolysis in vitro at thefollowing ranges.

TABLE III NIMEL OUTPUT BEAM ENERGY POWER POWER SPOT TREAT- DENSITYDENSITY (W) 6 CM MENT TOTAL (RADIANT (IRRA- 870 NM + DIAM- TIME ENERGYEXPOSURE) DIANCE) 930 NM ETER (SEC) (JOULES) (J/CM²) (W/CM²) Plate 728.26  10 min 480 J 16.7 J/cm² 0.027 0.4 W + cm2 600 sec W/cm² 0.4 WTime After Irradiation Plate (min.) Treated 1 Control 1 Control 2Glycerol Concentrations Gly Conc. (micro. M) 7 30 20.0000 21.538517.6923 7 60 41.9231 45.0000 38.4615 Free Fatty Acid Concentrations FFAConc. (micro. M) 7 30 99.0000 119.8333 104.8333 7 60 175.6667 207.3333179.8333 Relative Glycerol Relative Free Fatty Acid ConcentrationsConcentrations (Percent of control) (Percent of control) Time After TimeAfter Irradiation Irradiation Plate (Min.) T1 % Cont Plate (Min.) T1 %Cont 7 30 113.04 7 30 94.44 7 60 109.00 7 60 97.68

The Control single wavelength of 810 nm demonstrates little effect toslight suppression of Lipolysis in vitro at the following ranges.

TABLE IV NIMEL BEAM ENERGY DENSITY OUTPUT SPOT TOTAL (RADIANT POWERDENSITY POWER (W) 6 CM TREATMENT ENERGY EXPOSURE) (IRRADIANCE) 810 NMDIAMETER TIME (SEC) (JOULES) (J/CM²) (W/CM²) Plate 3 28.26 cm²  20 min600 J 20.4 J/cm² 0.017 W/cm² 0.5 W 1200 sec Glycerol Concentrations FreeFatty Acid Concentrations Plate, Gly Conc Plate, FFA Conc time after(microM) time after (microM) irradiation Parameters T1 C1 irradiationParameters T1 C1 6, 15 min 810 nm, 14.6154 12.3077 6, 15 min 810 nm,18.1667 31.5000 0.5 W, 0.5 W, 1200 sec, 1200 sec, 6, 75 min 810 nm,26.1538 29.6154 6, 75 min 810 nm, 89.0000 119.0000 0.5 W, 0.5 W, 1200sec, 1200 sec,

Dosimetry Values for Optical Augmentation of Leptin Secretion

The single wavelength of about 930 nm demonstrates approximately 43%Augmentation of Leptin Secretion in vitro at the following range duringaugmented lipolysis.

TABLE V ENERGY NIMEL BEAM DENSITY POWER OUTPUT SPOT TOTAL (RADIANTDENSITY POWER (W) 6 CM TREATMENT ENERGY EXPOSURE) (IRRADIANCE) 930 NMDIAMETER TIME (SEC) (JOULES) (J/CM²) (W/CM²) Plate 3 28.26 cm2 20 min600 J 20.4 J/cm² 0.017 W/cm² 0.5 W 1200 sec Leptin Concentrations(pg/mL) - Calculations Plate Parameters T Ave C Ave NC Ave % of Control1 930 nm, 0.5 W, 600 sec, 6 cm Dia 23.6111 30.0000 33.3333 78.7% 2 930nm, 0.5 W, 900 sec, 6 cm Dia 41.3889 41.1111 21.9444 100.7% 3 930 nm,0.5 W, 1200 sec, 6 cm Dia 17.5000 12.2222 20.5556 143.2% 5 870 nm, 0.5W, 1200 sec, 6 cm Dia 25.2778 28.0556 31.1111 90.1% 6 810 nm, 0.5 W,1200 sec, 6 cm Dia 44.4444 36.1111 33.6111 123.1%

Dosimetry Values for Optical Augmentation of Leptin Secretion

The single wavelength of about 810 nm demonstrates approximately 23%Augmentation of Leptin Secretion in vitro at the following range duringnormal lipolysis as shown in Table V above.

Other embodiments of the disclosure will be apparent to those skilled inthe art from consideration of the specification and practice of thedisclosure disclosed herein. It is intended that the specification andexamples be considered as exemplary only, with a true scope and spiritof the disclosure being indicated by the following claims.

1. A method of reducing lipid level in an adipocyte without generatingsignificant heat in, or significant damage to the adipocyte, comprisingthe step of irradiating a target site on an individual's skin aboveadipose tissue with an optical radiation having a first wavelength fromabout 850 nm to about 879 nm and/or a second wavelength of about 905 nmto about 945 nm at a dosimetry from about 0.015 W/cm̂2 to 1 W/cm̂2 tomodulate at least one of the innate biochemical processes of adipocytes.2. The method according to claim 1, wherein at least one of thebiochemical processes had already been initiated with exercise and/or bypharmacological means before the irradiation.
 3. The method according toclaim 1, wherein at least one of the biochemical processes of adipocytesis selected from lipolysis, lipogenesis, leptin production, adiponectinproduction, and glucose uptake.
 4. The method according to claim 1,wherein the optical radiation has a wavelength from about 865 nm toabout 875 nm and/or about 925 nm to about 935 nm.
 5. The methodaccording to claim 1, wherein the optical radiation is provided for atime of from about 10 to about 120 minutes.
 6. The method according toclaim 1, wherein the optical radiation is provided for a time of fromabout 15 to about 100 minutes.
 7. The method according to claim 1,wherein the optical radiation is provided for a time of from about 20 toabout 80 minutes
 8. The method according to claim 1, wherein thedosimetry provides an energy density from about 10 J/cm̂2 to about 10,000J/cm̂2 at the skin surface above the adipose tissue.
 9. The methodaccording to claim 1, wherein the dosimetry provides an energy densityfrom about 50 J/cm̂2 to about 8,000 J/cm̂2 at the skin surface above theadipose tissue.
 10. The method according to claim 1, wherein thedosimetry provides an energy density from about 100 J/cm̂2 to about 5,000J/cm̂2 at the skin surface above the adipose tissue.
 11. The methodaccording to claim 1, further comprising delivering the opticalradiation to the target site by one or more LEDs or LED arrays withaspheric collimating lenses within an article of clothing or a wrap. 12.The method according to claim 1, further comprising delivering theoptical radiation to the target site by one or more LED arrays withaspheric collimating lenses within an article of clothing or a wrap wornby the individual.
 13. The method according to claim 1, whereindifferent biochemical processes within the adipocytes that are normallyantagonistic to each other will then function synergistically.
 14. Themethod according to claim 13, wherein the biochemical processes thatwill then function synergistically can modulate alternative lipolytic orlipogenic pathways within the adipocytes.
 15. A device for reducing fatcomprising at least one optical light source which emits an opticalradiation having a wavelength from about 850 nm to about 879 nm and/orfrom about 905 nm to about 945 ran at a dosimetry from about 0.015 W/cm̂2to 1 W/cm̂2, wherein said at least one optical light source is attachedto an item of clothing.
 16. The device according to claim 15 wherein thearticle of clothing is selected from a belt, a wrap, a bandage, pants,shorts, belt, wrap, arm band, leg band, and a shirt.
 17. The deviceaccording to claim 15, wherein it is incorporated into a piece of anexercise equipment or other apparatus as an accessory item.
 18. Thedevice according to claim 15, wherein the wavelength band is betweenabout 850 nm and about 879 nm and/or between about 900 nm and about 940nm.
 19. The device according to claim 15, wherein the power density isbetween 0.015 W/cm̂2 to 1 W/cm̂2.
 20. The device according to claim 15,wherein the optical radiation is coherent. 21-44. (canceled)